Use of cortisol antagonists in the treatment of heart failure

ABSTRACT

The present invention relates to the use of a cortisol antagonist in the manufacture of a medicament for the treatment of heart failure as well as to a method of treating heart failure which comprises administration of a cortisol antagonist and to a product containing (a) a cortisol antagonist and (b) a second drug as a combined preparation for simultaneous, separate or sequential use in the treatment of heart failure or in improving cardiac function and reducing exercise intolerance.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a national stage filing of International PatentApplication PCT/GB00/02551, filed 3 Jul. 2000, which claims priorityfrom Great Britain Patent Application 9915625.9, filed 2 Jul. 1999.

The present invention relates to heart failure and in particular to theuse of a particular class of compounds for the treatment of heartfailure.

Heart failure, which is generally characterised by impaired cardiacfunction and exercise intolerance affects a very large number of peopleworldwide, particularly in the Western world. Heart failure and itscomplications are responsible for premature death in a proportion ofsufferers and generally curtails the working life and range ofactivities which can be undertaken by the sufferer, as wellsignificantly reducing overall quality of life. Heart failure is foundin both sexes, young and old but is particularly prevalent in males andelderly or middle aged people.

Heart failure may be caused by a number of different underlying heartdiseases. Heart diseases and events which may be a factor in causingheart failure include valvular heart disease, valvular stenosis, heartmuscle disease, myocardial ischemia or infarction, cardiomyopathia andinfiltrative process or inflammatory process of either the muscle,endocardium or epicardium of the heart.

As heart failure is a common and serious condition, significant effortshave been made by the medical community towards developing treatmentsfor heart failure. A successful treatment should improve quality oflife, prevent or slow progression of cardiac dysfunction and prolonglife. Non-pharmacological treatments include modified diets to reducesodium retention and cause weight loss and exercise programmes, althoughthere is a conflict between the need to improve ventricular performancewhich is aided by bed rest and a desire to improve exercise intoleranceand maintain conditioning which is favoured by a moderate exerciseregime. In some cases heart failure will be treated by surgical meansincluding full heart transplantation.

A number of pharmaceuticals are available for the treatment of heartfailure and for the most part these fall into three broad categories,diuretics, vasodilators and inotropic drugs. Diuretic therapy seeks tomaintain intravascular volume at the lowest level compatible withoptimal cardiac performance. A reduction in intravascular volume has theadvantage of reducing interstitial fluid by allowing its reabsorptioninto the vascular space. Furosemide and/or metolazone have been used asdiuretics in the treatment of heart failure but the use of these andother diuretics may lead to an undesirable drop in intracellularpotassium levels. Potassium levels should be monitored and potassiumsupplementation may be required.

Vasodilator drugs may be useful in increasing stroke volume due to areduction in vascular impedance and in reducing preload due to anincrease in venous capacitance. Optimal treatment using vasodilatorswill often require coadministration of an arterial dilator such ahydralazine or minoxidil and a venodilator such as isosorbide dinitrate.

Treatment with a diuretic and/or vasodilator may be supplemented by aninotropic drug such as digoxin, dobutamine or aminone.

In addition, a patient suffering from heart failure may, in certaincircumstances be prescribed antiarrhythmic drugs, β-adrenoreceptorblockers, anticoagulants, an angiotensin-converting enzyme (ACE)inhibitor or an angiotensin II antagonist.

While a large number of pharmaceuticals are available to the physicianfor treating heart failure, different patients will have different needsand successful treatment will often require administration of a range ofcomplementary drugs. Adverse reactions by some patients to particulardrugs and drug intolerance means there is a continuing demand for newdrugs of use in the treatment of heart failure, as physicians strive tofind the best drug or combination of drugs for each sufferer. Moreover,heart disease is so widespread that the public and doctors alike demandever more effective methods of treatment which can provide a higherquality of life for longer periods.

It has now surprisingly been found that administration of a cortisolantagonist is effective in the treatment of heart failure and symptomsassociated with heart failure.

Thus, in one aspect, the present invention provides the use of acortisol antagonist for the manufacture of a medicament for thetreatment of heart failure.

‘Heart failure’ can be defined clinically as a syndrome of ventriculardysfunction accompanied by reduced exercise capacity. Typically, thereis a characteristic pattern of hemodynamic, renal and neural responses.In effect, heart failure is the inability of the heart to pump blood atan adequate rate to fulfill tissue metabolic requirements or the abilityto do so only at an elevated filling pressure. Heart failure typicallyresults in an inability to drain away body fluid which may cause ascites(body fluid in abdominal cavity), this often being observed in backwardheart failure and when the liver is swollen. Within this generaldefinition, it is intended to include the following types of heartfailure and cortisol antagonists are suitable for use in treating all ofthese:

Acute congestive heart failure, a rapidly occurring deficiency incardiac output marked by venocapillary congestion, hypertension andoedema, usually pulmonary oedema.

Backward heart failure, a concept of heart failure stating thatimbalance of performance of the ventricles due to dysfunction of oneresults in a rise in pressure behind that ventricle, with backwardtransmission of the increased pressure and consequent rise in venouspressure and distension.

Congestive heart failure (CHF), a clinical syndrome due to heartdisease, characterised by breathlessness and abnormal sodium and waterretention, often resulting in oedema. The congestion may occur in thelungs or peripheral circulation or both, depending on whether the heartfailure is right-sided or general.

Diastolic heart failure, heart failure due to a defect in ventricularfilling caused by an abnormality in diastolic function.

Forward heart failure, a concept of heart failure that emphasizes theinadequacy of cardiac output relative to body needs; oedema isattributed primarily to renal retention of sodium and water, and venousdistention is considered a secondary feature.

High-output heart failure, heart failure in which the cardiac outputremains high enough to maintain a brisk circulation with warmextremities but is inadequate to meet demand; it is most oftenassociated with hyperthyroidism, anemia, arteriovenous fistulas,beriberi, osteitis deformans or sepsis.

Left-sided heart failure, left ventricular failure, failure of adequateoutput by the left ventricle despite an increase in distending pressureand in end-diastolic volume, with dyspnea, orthopnea and other signs andsymptoms of pulmonary congestion and oedema.

Low-output heart failure, heart failure in which cardiac output isdecreased, as in most forms of heart disease, leading to clinicalmanifestations of impaired peripheral circulation and peripheralvasoconstruction (cold, pale extremities, cyanosis, narrowed pulsepressure).

Right-sided heart failure, right ventricular failure, failure of properfunctioning of the right ventricle, with venous engorgement, hepaticenlargement, and subcutaneous oedema; it is often combined withleft-sided heart failure.

Systolic heart failure, heart failure due to a defect in expulsion ofblood caused by an abnormality in systolic function.

A cortisol antagonist is particularly well suited to the treatment ofcongestive, diastolic, backward, low-output and right-sided heartfailure. Thus, the treatment of these conditions represents a preferredaspect of the present invention.

According to the New York Functional Classifications (Ganiats, T. G.,Browner, D. K., Dittrich, H. C. in American Heart Journal (1998) 135: 5Pt 1, 819-824) the severity of heart failure can be divided into fourclasses as follows:

-   -   Class I—no limitation of physical activity: ordinary physical        activity does not cause undue fatigue, shortness of breath or        palpitation;    -   Class II—slight limitation of physical activity; such patients        are comfortable at rest, ordinary physical activity results in        fatigue, shortness of breath, palpitations or angina;    -   Class III—marked limitation of physical activity; although        patients are comfortable at rest, less than ordinary activity        will lead to symptoms;    -   Class IV—inability to carry out any physical activity without        discomfort: symptoms of congestive heart failure are present        even at rest. With any physical activity increased discomfort is        experienced.

Cortisol antagonists are suitable for the treatment of all classes ofheart failure, particularly classes II to IV.

By ‘cortisol antagonist’ is meant any compound or agent which reducesproduction of cortisol or circulating levels of biologically activecortisol or which limits the biological effects of cortisol byinhibiting cortisol (glucocorticoid) receptors competitively ornon-competitively, or in any other way. The term includes agents whichinterfere with the regulation of cortisol synthesis along the so-calledhypothalmic-pituitary-adrenal gland (HRA) axis. Thus a “cortisolantagonist” may broadly be regarded as any compound or agent whichantagonises or inhibits (i.e. reduces or prevents) cortisol activity.

A large number of agents are known to suppress glucocorticoid productionor inhibit their receptor binding in humans: sodium valporate(Aggernaes, H. et al. Acta Psychïatr. Scand. (1988) 77 170-174);Enkephalins and their synthetic analogues (Stubbs, W. A. et al. TheLancet (1978) 1225-1227); Opioids such as loperamide, commerciallyavailable under the trademark IMODIUM from Janssen Pharmaceutica N.V.;the antihypertensive drug Clonidine (Slowinska-Srzednicka, J. et al.European Journal of Clinical Pharmacology (1988) 35 115-121); Oxytocin(Legros, J. J. et al. Endocrinologica (1987) 114 345-349) andMifepristone, known as RU 486 or RU 38486 available from Roussel-Uclaf.Mifepristone and other antagonists which operate at the receptor levelare a class of preferred active agents for use in the present invention.

Any of the above agents or any of the large number of cortisol synthesisinhibitors known in the art, e.g. econazole (Squibb, U.K.), ketoconazoleand miconazole (Janssen, Belgium) and their derivatives, may be used ascortisol antagonists according to the present invention. In the case ofeconazole and miconazole, derivatives of these particular compounds arepreferred.

‘Derivatives’ encompass compounds which are structurally related to theprimary compound (e.g. ketoconazole) but are functionally equivalent orsuperior. Thus, a derivative might have a slightly inferior therapeuticactivity but be a useful molecule because it exhibits reduced toxicity,is more convenient to formulate or administer etc. Derivatives mayinclude salts or other variants which have been more significantlymodified while retaining functionally important structural motifs incommon with the primary compound. In the case of econazole andmiconazole, such derivatives may exhibit better overall properties thanthe primary compounds in terms of therapeutic activity and toxicity, forexample.

Preferred cortisol antagonists include those compounds which inhibit thesynthesis of cortisol, either by reducing the production of cortisol inany form or which cause the production of a modified form of cortisolwhich is less biologically active than native, naturally occurringcortisol. Preferably, cortisol synthesis inhibitors will act on thecortisol synthetic pathway in a way which does not significantly affectthe normal production of the other steroid hormones, in particular whichdoes not significantly effect production of mineralocorticoids such asaldosterone. The ‘significance’ of the effect is considered in terms ofthe biological, in vivo, effect. Ketoconazole and its derivatives arepreferred for use according to the invention and in addition, isomers ofketoconazole are known and may be used, individually or in combination(Rotstein et al., J. Med. Chem. (1992) 35, 2818-2825). The Cis-2S,4R andCis-2R,4S isomers are particularly preferred for use in accordance withthe present invention. These isomers may be used individually or incombination as in the commercially available product Fungoral™(Janssen-Cilag, Belgium).

In the case of cortisol antagonists which act via cortisol(glucocorticoid) receptors, the antagonist will preferably have aneffect on the receptors in the kidney and/or the heart. The bindingaffinity which an antagonist has for receptors in different organs maynot be uniform and preferably the antagonist used in the presentinvention will have a comparatively higher binding affinity for theglucocorticoid receptors in the heart and/or kidney.

The cortisol antagonists for use according to the present invention havea sufficiently negative effect on circulating levels of biologicallyactive cortisol or on its biological efficacy to cause a measurable andsignificant improvement in heart failure or its associated symptoms. Itis not expected that in all cases treatment will be totally successfulbut “treatment” according to the present invention should includeimprovement in one or more of the following areas: fluid retentionincluding oedema of lower limbs and fluid in the lungs (pulmonaryoedema), dyspnea, liver enlargement, heart rate, stroke volume,shortness of breath, exercise intolerance and general physical andmental health. Particularly, improvements are seen in symptomsassociated with fluid retention (e.g. liver enlargement, peripheral andpulmonary odema and ascites).

Advantageously, according to the uses and method of the presentinvention, one or more of the following benefits may be achieved:

-   -   a 10% or more reduction in liver size,    -   a 10% or more reduction in heart rate,    -   a 15% or more improvement in physical health        according to the test described in the Examples herein.

Further symptoms which often occur with heart failure, whatever thecause, are enlargement of the heart and development of a fibrosis in theheart muscle. These morphological aspects of heart failure can also betreated successfully by administration of a cortisol antagonist.

Heart failure will be diagnosed when a patient has impaired cardiacfunction and exercise intolerance. All patients with heart failure,whether newly diagnosed or at a more advanced stage can be consideredfor treatment in accordance with the present invention. Treatment with acortisol antagonist may be successful whatever the underlying diseasewhich has resulted in a diagnosis of heart failure. The observationswhich have resulted in the present invention relate to the treatment ofheart failure itself and its symptoms not to the diseases and riskfactors which may give rise to heart failure. Various medical conditionssuch as cardiovascular disease may or may not lead to heart failure butas the implications for untreated heart failure are serious, it isbeneficial to have available treatments specifically for heart failureand its associated symptoms.

Thus, in a further aspect is provided a method of treating heart failurein a mammal which method comprises administering a pharmaceuticallyeffective amount of a cortisol antagonist to said mammal.

Alternatively viewed, according to the method of the invention, anamount of cortisol antagonist is administered which is effective toimprove one or more of the symptoms of heart failure; these areas inwhich improvement may be observed are discussed above.

A ‘pharmaceutically effective’ amount can be determined with referenceto the various areas discussed herein in which treatment may providemeasurable improvements, and selected with reference to the Examples andstandard practices for deciding dosage amounts.

Generally, patients in need of such a treatment will be diagnosed assuffering from heart failure by reference to the clinical definitionsprovided herein or other medically accepted criteria.

The cortisol antagonist or antagonists may be administered to thepatient in any convenient form, orally or by intravenous, enteral orparenteral routes. Preferably the cortisol antagonist will beadministered by oral routes.

Alternatively viewed, the invention provides a method of improvingcardiac function and reducing exercise intolerance in a mammal whichmethod comprises administering a pharmaceutically effective amount of acortisol antagonist to said mammal.

Likewise, the invention provides the use of a cortisol antagonist in theproduction of a medicament for improving cardiac function and reducingexercise intolerance.

An improvement in cardiac function may include a reduction in heart rateand/or an increase in stroke volume. Exercise intolerance is generallycharacterised by breathlessness and other signs of fatigue, cramp etc.,primarily due to an inability of the patient suffering from heartfailure to supply sufficient oxygenated blood to muscle and other organsand tissue. It can be measured by a subnormal physical exercise test(Faggiano, P., D'Aloia, A., Gualeni, A. and Giordano, A. AmericanJournal of Cardiology (1998) 15 81:4, 437-42).

Compositions comprising a cortisol antagonist as defined above arepreferably formulated prior to administration.

The present invention therefore also provides a pharmaceuticalcomposition for use in the treatment of heart failure, said compositioncomprising a cortisol antagonist together with at least onepharmaceutically acceptable carrier, diluent or excipient. The activeingredient in such compositions may comprise from 0.05% to 99% by weightof the formulation, more preferably 0.1% to 1.0%.

By “pharmaceutically acceptable” is meant that the ingredients must becompatible with other ingredients of the composition as well asphysiologically acceptable to the recipient.

The pharmaceutical compositions may be formulated according to any ofthe conventional methods known in the art and widely described in theliterature. Thus, the active ingredient may be incorporated, optionallytogether with other active substances, with one or more conventionalcarriers, diluents and/or excipients, to produce conventional galenicpreparations such as tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments, soft and hard gelatincapsules, suppositories, sterile injectable solutions sterile packagedpowders, and the like.

Examples of suitable carriers, excipients, and diluents are lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, aglinates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, water, water/ethanol, water/glycol, water/polyethylene, glycol,propylene glycol, methyl cellulose, methylhydroxybenzoates, propylhydroxybenzoates, talc, magnesium stearate, mineral oil or fattysubstances such as hard fat or suitable mixtures thereof. Thecompositions may additionally include lubricating agents, wettingagents, emulsifying agents, suspending agents, preserving agents,sweetening agents, flavouring agents, and the like. The compositions ofthe invention may be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art. Sustained and/ordelayed release formulations may be particularly convenient.

The active agents are preferably formulated into tablets, each tabletcontaining a predetermined amount of active ingredient.

Suitable doses will vary from patient to patient and can be determinedby the physician in accordance with the weight, age and sex of thepatient and the severity of the condition and also the particularantagonist selected. A typical total daily dose will be in the region of50 or 100-1200 mg of a cortisol antagonist which may be administered asa single dose or in several smaller doses during the day. Typical singledoses will be in the region of 100-800 mg. Administration mayadvantageously be at around 10.00 p.m. in order to reduce cortisolactivity during the night when natural cortisol levels are at theirhighest. Ketoconazole is preferably administered as a daily dose of200-1000 mg, e.g. 300-600 mg.

During the majority of the treatment period, typically 75% or more,effective treatment will be daily. By ‘effective treatment’ is meantthat the circulating levels of the cortisol antagonist are atphysiologically effective levels; this may be achieved by dailyadministration or, for example, by use of a controlled-releasedformulation which offers sustained release over several days or more.

Improvements in patients treated in accordance with the presentinvention may be seen immediately or after some (e.g. 2-4) weeks andtreatment should normally be continued for 3 months or more to achievemaximum benefits. As with most treatments for heart failure, it may benecessary to administer the cortisol antagonist for the rest of thepatient's life. Such long term treatment may not necessarily becontinuous and the optimum dose may vary during the course of treatment.

Use of a cortisol antagonist may be in place of or in addition to use ofother drugs for the treatment of heart failure. This may improve theefficacy of the overall treatment regime and/or reduce the amount ofdrugs required by the patient or enable the physician to ceaseadministration of a drug which is causing undesirable side effects.

As well as treatments which comprise the coadministration of a cortisolantagonist and one or more other drugs for the treatment of heartfailure, medicaments and treatments in accordance with the presentinvention may comprise more than one cortisol antagonist. Treatment mayinvolve administration of an antagonist which affects synthesis ofcortisol in the adrenal glands and also treatment with an antagonistwhich inhibits the activity of cortisol at the receptor level.Furthermore treatment may involve administration of an antagonist whichoperates along the HPA axis as mentioned above.

Thus, in a further aspect the present invention provides a productcontaining (a) a cortisol antagonist and (b) a second drug (e.g. asecond agent effective in the treatment of heart failure) as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of heart failure or in improving cardiac function and reducingexercise intolerance.

Suitable ‘second drugs or agents’ include known drugs for use in thetreatment of heart failure as are discussed above e.g. diuretics,vasodilators, inotropic drugs, ACE inhibitors and angiotensin IIantagonists and also a second cortisol antagonist as defined herein.

Where two or more active agents are administered, they may be givensimultaneously to the patient or times of administration may bestaggered throughout the day or treatment cycle.

The invention will be further described with reference to the followingnon-limiting Examples.

EXAMPLE 1

Subject 1: A 44 year old man exhibiting the symptoms of heart failure,including retention of body fluid manifested as moderate oedema of lowerlimbs and body fluid in the lungs. Also, moderate dyspnea and increasedheart rate as well as an increase in liver size (indicative of fluidretention in the liver). Patient being treated for heart failure withlisinopril (Zestril®)Treatment: 400 mg of a racemate of the Cis-2S,4R and Cis-2R,4S isomersof ketoconazole (Fungoral™ tablets—Janssen-Cilag, Belgium) wasadministered at 10.00 pm every day for a 3 month period.Observations: Body weight reduced by 3.8 kg—attributable to a reductionin fluid retention.Heart rate fell from 72 beats/min to 62 beats/min.Reduction in liver size of 10% and a resulting reduction in livertransaminases

-   S-ASAT reduced from 0.44 to 0.30 μKat/L-   S-ALAT reduced from 1.0 to 0.39 μKat/L    Dyspnea, oedema of lower limbs and body fluid in the lungs reduced.    Physical health as measured by a subnormal physical exercise test    (Faggiano, P. et al. supra) improved by 15%.    Dose of lisinopril (Zestril®) could be reduced to half of original    dose

EXAMPLE 2

Subject 2: A 63 year old woman exhibiting the same symptoms of heartfailure as subject 1. Patient being treated for heart failure withfurosemid (40 mg/day)

Treatment: As for Example 1.

Observations: Body weight reduced by 4.2 kg.

Heart rate fell from 74 beats/min to 60 beats/min.

Reduction in liver size of 15% and in liver transaminases.

-   S-ASAT reduced from 0.58 to 0.32 μKat/L-   S-ALAT reduced from 0.92 to 0.68 μKat/L    Dyspnea, oedema of lower limbs and body fluid in lungs reduced.    Physical health, as measured by a subnormal physical exercise test,    improved by 20%.    Dose of furosemid could be stopped within 6 weeks of commencement of    treatment with ketoconazole.

1. A method for the treatment of heart failure in a mammal whichcomprises administering a cortisol antagonist to said mammal in anamount effective to treat the heart failure, with the proviso that saidcortisol antagonist is not clonidine.
 2. The method of claim 1 whereinthe heart failure is selected from the group consisting of congestiveheart failure, diastolic heart failure, low-output heart failure,right-sided heart failure, cardiac hypertrophy, and cardiac fibrosis. 3.The method of claim 2 wherein the cortisol antagonist is an inhibitor ofcortisol synthesis.
 4. The method of claim 3 wherein the inhibitor ofcortisol synthesis is ketoconazole or a derivative thereof.
 5. Themethod of claim 4 wherein the cortisol synthesis inhibitor is aCis-2S,4R and/or Cis-2R, 4S isomer of ketoconazole.
 6. The method ofclaim 1, wherein the daily dose of cortisol antagonist beingadministered to the subject being treated is 100-1200 mg.
 7. The methodof claim 1, wherein the daily dose of cortisol antagonist beingadministered to the subject being treated is 100-800 mg.
 8. The methodof claim 1, wherein the cortisol antagonist is ketoconazole and thedaily dose of ketoconazole being administered to the subject beingtreated is 300-600 mg.
 9. A method for the treatment of one or moresymptoms associated with heart failure selected from the groupcomprising edema of lower limbs, pulmonary edema, dyspnea, liverenlargement, increased heart rate, reduced stroke volume, shortness ofbreath and exercise intolerance which comprises administering, in adaily dose, a cortisol antagonist to a mammalian subject, with theproviso that said cortisol antagonist is not clonidine.
 10. The methodof claim 9 wherein the symptom is pulmonary edema.
 11. The method ofclaim 9 wherein the daily dose of the cortisol antagonist administeredto the subject being treated is 100-1,200 mg.
 12. The method of claim 9wherein the daily dose of the cortisol antagonist administered to thesubject being treated is 100-800 mg.
 13. The method of claim 9 whereinthe cortisol antagonist is ketoconazole and the daily dose ofketoconazole being administered to the subject being treated is 300-600mg.